ExPDrug: Integration of an interpretable neural network and knowledge graph for pathway-based drug repurposing

Precision medicine aims to provide personalized therapies by analyzing patient molecular profiles, often focusing on gene expression data. However, effectively linking these data to actionable drug discovery for clinical application remains challenging. In this paper, we introduce ExPDrug, a neural network (NN) model that integrates biological pathways from transcriptomic data with a biomedical knowledge graph to facilitate pathway-based drug repurposing. ExPDrug enhances disease phenotype prediction by capturing the complex relationships between genes and pathways. Using layer-wise relevance propagation (LRP), the model interprets the contribution of each pathway using relevance scores applied in a random walk-with-restart (RWR) algorithm to prioritize potential drug candidates in the biomedical network. ExPDrug outperforms existing methods in predicting phenotypes for the three diseases and identifying drug candidates, as supported by the literature. This model offers a transformative approach for advancing precision medicine by linking transcriptomic insights directly to clinical drug repurposing, thereby potentially improving treatment strategies for complex diseases.